Perioperative use of RAAS

Antagonists: Evidence and

Controversy

Moises Auron MD, FAAP

Department of Hospital Medicine
Cleveland Clinic
 Objectives
• Appraise the evidence supporting the
current perioperative management of
Renin-Angiotensin-Aldosterone system
(RAAS) antagonists in non-cardiac
surgery.
• Appraise the existence of newer RAAS
antagonists such as Aliskiren (direct renin
inhibitor) and its management in the
perioperative setting.
 Introduction
• The renin-angiotensin-aldosterone system
(RAAS) antagonists (RAAS-antagonists)
include:
– Angiotensin-converting enzyme inhibitors
(ACEI)
– Angiotensin II receptor subtype 1 blockers
(ARB)
– Direct renin inhibitors (Aliskiren)
– Aldosterone antagonists (Spironolactone,
Eplerenone)
 RAAS antagonists: indications
• Hypertension
• Congestive heart failure
• Coronary artery disease
• Diabetic nephropathy
• Prevention of progression of chronic renal
failure
Ann Intern Med. 2008 Jan 1;148(1):16-29.
J Card Fail. 2008 Apr;14(3):181-8.
J Gen Intern Med. 2006 Dec;21(12):1242-7.
Lancet. 2005 Dec 10;366(9502):2026-33.
Curr Pharm Des. 2007;13(13):1335-45.
 RAAS antagonists and surgery

• Intra-operative hypotension after induction

of anesthesia
• Post-operative acute renal failure
• Not associated with increased mortality
• All based on small studies

Anesth Analg. 1999 Nov;89(5):1143-55.

Anesth Analg. 2001 Nov;93(5):1111-5.
J Intern Med. 2008 Sep;264(3):224-36.
J Intern Med. 2008 Sep;264(3):224-36.
Pharmacology of RAAS antagonists:
perioperative implications
• Sympathetic blockade
• Increase in the bioavailability of the vasodilatory agents:
– Bradykinin
– Nitric oxide
– Prostacyclines
• Inhibition of the vasoconstrictor effects of angiotensin II
• Reduction in the secretion of aldosterone and ADH
– Decrease in renal salt and water reabsorption.
• Pleiotropic effects
– inhibition of the different angiotensin peptides as well as both
renin and pro-renin receptors

Circulation. 2000 Jul 18;102(3):351-6.

J Intern Med. 2008 Sep;264(3):224-36.
Effects of anesthesia on the BP
• Increased venous pooling of blood
• Decreased cardiac output
• Arterial hypotension.

Curr Pharm Des. 2003;9(9):763-76

 Intra-operative BP
• Maintained by:
– RAAS
– Sympathetic nervous system
– Arginine-vasopressine (AVP)
• Secretion stimulated as well by Angiotensin II

Curr Pharm Des. 2003;9(9):763-76

 Intra-operative BP
• Multilevel effect for maintenance of intra-
operative BP
– Adequate hydration
– Sympathomimetics
– AVP agonists (terlipressin)
 Pharmacogenomics of RAAS
• Genetic susceptibility to the RAAS-
antagonists affected by single nucleotide
polymorphism (SNP) mutations in:
– Angiotensinogen
– Angiotensin receptor 1
– Angiotensin receptor 2.
• Affects intraoperative hemodynamic
response to RAAS-antagonists.
Circulation. 2007 Feb 13;115(6):725-32.
J Mol Med. 2008 Jun;86(6):637-41.
ACEI

Am J Health Syst Pharm. 2004 May 1;61(9):899-912.

ARB

Circulation 2001;103;904-912.
EVIDENCE AGAINST
RAAS-ANTAGONISTS
 Cleveland Clinic: IMPACT
• Current practice: discontinue both ACEI and
ARB on the morning of surgery.
• Based on several small, controlled, randomized
studies which found an increased frequency of
refractory hypotension requiring intensive
intravenous fluids and vasopressors after the
induction of anesthesia when RAAS-antagonists
were not discontinued preoperatively.

Cleve Clin J Med. 2006 Mar;73 Suppl 1:S82-7.

 McCarthy
• Sublingual captopril (12.5 mg and 25 mg)
vs. placebo 25 minutes before ETI
• N = 40
• Captopril - increased ↓BP (P <0.05) within
3 minutes after ETI
– No significant difference between both doses.

Anaesthesia. 1990 Mar;45(3):243-5.

 Coriat
• HTN patients on chronic ACEI -
randomized 2 groups, - administration of
ACEI in AM of surgery vs. withdrawn.
• Requirement of ephedrine:
– Captopril (n = 36) 64% vs. 12% (P<0.05)
– Enalapril (n = 20) 100% vs. 18% (P<0.005)

Anesthesiology. 1994 Aug;81(2):299-307.

 Brabant
• Hemodynamic response to induction between
ARB, beta-blockers (BB), Ca channel blockers
(CB) and ACEI.
• ↓BP : SBP ↓ of > 30% from the preoperative
value or an absolute SBP < 90 mm Hg.
– ARB (12 of 12)
– BB/CB-treated patients (27 of 45)
– ACEI (18 of 27) (P< 0.05).
• ARB group – increased refractory to adrenergic agents (4 of
12) vs. BB/CB group (0 of 45) vs. ACEI (1 of 27).
• ↓BP - responsive to a vasopressin agonist.

Anesth Analg. 1999 Dec;89(6):1388-92.

 Bertrand
• Patients on chronic therapy with ARB (N = 37)
• 18 D/C ARB the day before sx vs. 19 received
ARB 1 h prior to induction.
• ARB in AM of surgery - > frequent episodes and
longer duration of ↓BP.
– ↓BP - refractory to adrenergic agents, requiring
terlipressin.
– ARB dose < 10 hours of induction - > frequent
hypotensive episodes.

Anesth Analg. 2001 Jan;92(1):26-30.

 Comfere
• Patients on chronic anti-HTN treatment
with ACEI/ARB (N = 267)
• Incidence of ↓BP during the first 30
minutes after induction of anesthesia was
more frequent in patients whose most
recent ACEI/ARB was taken < 10 h. (60%
vs. 46%, O.R. 1.74 (95% C.I. 1.03 to 2.93,
P = 0.04)
Anesth Analg. 2005 Mar;100(3):636-44.
 Shirmer
• Patients on chronic antiHTN with ACEI (N
= 100) RCT.
• 50 received ACEI in AM of surgery vs. 50
who didn’t.
• BP and HR were significantly lower in the
ACEI group requiring supportive
adrenergic agonists
– 17 of 50 in the ACEI vs. 5 of 50 in the
withdrawal group.
Anaesthesist. 2007 Jun;56(6):557-61.
 Licker
• Pts with CAD undergoing non-cardiac surgery
• N = 32; 16 receiving chronic ACEI and 16 didn’t.
• Induction-related ↓BP: 9 (ACEI) vs. 2 (control).
– Diminished response to phenylephrine in the ACEI
group.
– Decreased -adrenergic vasoconstrictive response?

Can J Anaesth. 2000 May;47(5):433-40.

 Kheterpal
• Prospective observational study: N=
12,381
• Diuretics + ACEI/ARB increased ↓BP and
requirement for vasopressors vs. ACEI
alone or when combination with Ca-vs.
• Propensity score matching and ROC
curve analysis was done to control for
comorbidities that may acquaint for
hemodynamic variations between groups.
J Cardiothorac Vasc Anesth. 2008 Apr;22(2):180-6.
 Rosenman
• Systematic review
• Random-effects meta-analysis (incorporates
within-study and between-study variability)
• 5 studies; N = 434
• Preoperative RAAS-antagonists on the day of
surgery – increased likelihood of ↓BP requiring
vasopressors after induction (RR 1.50, 95% CI
1.15 to 1.96).
• No difference noted in incidence of peri-
operative MI between groups (RR 0.41, 95% CI
0.07 to 2.53).
J Hosp Med. 2008 Jul;3(4):319-25.
Metaanalysis: Hypotension

J Hosp Med. 2008;3:319–325

Metaanalysis: AMI

J Hosp Med. 2008;3:319–325

 EVIDENCE
SUPPORTING RAAS-
ANTAGONISTS
• None of the studies showed any
significant difference in postoperative
complications.
• No proof of association between ↓BP and:
– Major CV complications
– Stroke
– Renal failure
– ICU LOS
– Increased mortality
• Heropoulos
– Assessment of hemodynamic and hormonal responses to:
• ETI
• Incision
• Limb-tourniquet inflation
– RCT; N = 30 patients undergoing limb surgery
– Enalaprilat vs. placebo.
• - 1.25 mg IV 20 min prior to induction vs. 0.625 mg IV at the onset of
tourniquet-associated hypertension.
– Venous blood samples for PRA and catecholamine (pre-
intubation, 3 min post-intubation, 3 min post-incision, at onset of
tourniquet hypertension, 3 min post-extubation and 1 hr
postoperatively)
• No significant differences in catecholamine levels.

Anesth Analg. 1995 Mar;80(3):583-

90.
Drugs. 2007;67(7):1053-76.
 Tohmo and Karanko
• Pre-operative enalapril in balanced hypotensive
anesthesia for cerebrovascular surgery.
• Controlled ↓BP - minimize intraoperative
bleeding. RCT vs. placebo.
• Enalapril ↓ HTN response to ETI, ↓
postoperative vasodilators, more stable BP
control.
• “Preoperative fasting may be the contributor to
peri-operative ↓BP - improper fluid balance and
Na2+ depletion - prevented by ensuring proper
intravascular volume status”
J Neurosurg Anesthesiol. 1993 Jan;5(1):13-21.
Acta Anaesthesiol Scand. 1996 Jan;40(1):132-3.
 ACE and Atrial Fibrillation
• Non surgical patients - ACEI - 50% reduction in
the risk of developing new-onset atrial fibrillation
(AF)
• White
– Preop ACEI or ARB and postop AF following cardiac
surgery (CABG or valvular surgery)
– N = 338 patients (175 (51.8%) received preoperative
ACEI or ARB).
– No association found between preop ACEI/ARB and
reduction in postop AF (adjusted OR 0.71, 95% CI
0.42 to 1.20).
– Larger number of patients is needed.

Eur J Cardiothorac Surg. 2007 May;31(5):817-20.

 Boldt
• RCT (N = 88)
• CABG
• 4 groups of 22 patients each
– intravenous enalapril
– enoximone (phosphodiesterase inhibitor)
– clonidine
– placebo (normal saline).
• Enalapril - following induction of anesthesia -
lower levels of cardiac enzyme release
– Cardioprotective effect of RAAS-antagonists against
ischemia/reperfusion injury

Heart. 1996 Sep;76(3):207-13.

 Pigott
• N = 40 patients undergoing CABG
• All patients were on chronic ACEI
– 20 continued
– 20 suspended
• No significant difference between the groups in
the frequency of hypotension during anesthesia.
• The group that withheld ACEI had postoperative
hypertension that required vasodilators

Br J Anaesth. 1999 Nov;83(5):715-20.

PERI-OPERATIVE RAAS-
ANTAGONISTS AND
RENAL FUNCTION
 Colson
• RCT (N = 18)
• Short-term (2 days) pre-op captopril vs.
placebo in CABG
• Captopril - better preserved RPF and GFR
during CPB vs. placebo treated patients.

Anesthesiology. 1990 Jan;72(1):23-7.

 Licker
– RCT (N = 20)
– 11 – i.v. enalapril 50 mcg/kg; 9 – NS 0.9% at
induction of anesthesia for aortic surgery.
– After infra-renal aortic cross
• Enalapril - ↑ DO2, ↑ splachnic perfusion, ↑GFR @
24 h post-op. (43)

Br J Anaesth. 1996 May;76(5):632-9.

 Benedetto
• RCT (N= 536)
• Effect of pre-op ACEI on AKI (↓GFR >
50%) – CABG.
• Preop ACEI (N = 281) - ↓ post-op AKI
(O.R. 0.48; 95% CI, 0.23 to 0.77; P <
0.04)
• Incidence of AKI requiring dialysis:
– 2.4% in ACEI group vs. 6.3% in controls (P =
0.03). (44) Ann Thorac Surg. 2008 Oct;86(4):1160-5.
 Cittanova
• Prospective study (N = 249) - aortic
surgery
• Chronic treatment with ACEI (withheld in
AM) - only factor associated with
significative postoperative renal
impairment (O.R. 2.01 95% C.I. 1.05 to
3.83)

Anesth Analg. 2001 Nov;93(5):1111-5.

 Kincaid
• Retrospective (N= 1209) – CABG
• Preop ACEI along with intra-op aprotinin –
ARF (OR 2.9, 95% CI 1.4 to 5.8, P <
0.0001).

Ann Thorac Surg. 2005 Oct;80(4):1388-93

RAAS-ANTAGONISTS IN
NEURAXIAL ANESTHESIA
• Thoracic epidural anesthesia – resultant
↓BP from attenuation of efferent
sympathetic drive
– ↑ vasopressin concentrations
– renin activity remains unchanged.

Eur J Anaesthesiol. 1992 Jan;9(1):63-9.

Anesthesiology. 1994 May;80(5):992-9.
• Hohne
– Assessment of the initial (first 20 minutes)
hemodynamic effect of ACEI in spinal
anesthesia for lower body procedures.
– RCT (21 on chronic ACEI vs. 21 control)
– Decrease in BP was similar.
– Plasma vasopressin and norepinephrine
levels increased.

Acta Anaesthesiol Scand. 2003 Aug;47(7):891-6.

 Aliskiren
• Direct renin inhibitor
• Long half life (30 - 40h)
• Increased renal vasodilatory effect vs.
ACEI and ARB. (59)
• Low oral bioavailability
– Terminal half life is 24 hrs.
• Weak antihypertensive (second-line
agent) J Am Coll Cardiol. 2008 Feb 5;51(5):519-28.
Circulation. 2008 Aug 12;118(7):773-84.
Am J Health Syst Pharm. 2008 Jul 15;65(14):1323-32.
 Conclusions
• RAAS-antagonists - associated with a variable
incidence of hypotension during the initial 30
minutes after induction of anesthesia in non-
cardiac surgery
• These hypotensive episodes have not been
linked to any significant postoperative
complications.
• The ACEI/ARB should be held at least 10 hours
or for one dose before the induction of
anesthesia.
 Conclusions (cont.)
• Careful hemodynamic monitoring
• Prevention of hypovolemia
• When to continue RAAS-antagonists?
– Complicated hypertensive patient
– Chronic heart failure of ischemic heart
disease
– Cardiac surgery
– Requires discussion with anesthesiologist